Breast cancer is the cause of thousands of deaths among females every year. (See A Snapshot of Breast Cancer, National Cancer Institute (August 2005)). Surgical intervention has saved the lives of many women. However, radical and partial mastectomies can be physically and emotionally debilitating. Surgery in combination with chemotherapy may still expose patients to the possibility of recurrence.
Massive research efforts have been directed to researching and developing drugs and other therapies (such as radiation, immunotherapy and vaccine) to treat and/or prevent breast cancer. Retinoic acid is a known metabolite of vitamin A. Retinoic acid and certain analogs thereof appear to be necessary for maintenance of normal epithelial tissue differentiation. Such analogs of retinoic acid may also be able to reverse the metaplastic condition of hamster trachea in vitamin A deficient epithelial tissue. (See Newton et al., Cancer Res 40:3413-3425 (1980)). Retinoic acid and certain amide analogs thereof have also been investigated for use as chemotherapeutic agents. (See Moon et al., Cancer Res 39:1339-1346 (1979)). Other retinoic acid analogs such as retinyl acetate, 13-cis-retinoic acid and glucuronide analogs have also been shown to display some cancer preventive activity including breast cancer preventive activity. (See Hill D L et al., Ann Rev Nutrition, 12:161-181 (1992))(See also Mehta R G et al., Oncology, 48:1505-1509 (1991)). Stilbene derivatives of retinoic acid have been suggested as possible agents for use in oncology. (See Simoni D et al., Retinoic Acid and Analogs as Potent Inducers of Differentiation and Apoptosis: New Promising Chemopreventative and Chemotherapeutic Agents in Oncology, Pure Appl Chem, 73:1437-1444 (2001)). Aromatic analogs of retinoic acid, such as 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl)-1-propenyl]benzoic acid (“TTNPB”), were also disclosed in Simoni et al.
The structure of retinoic acid (“RA”) is shown below.

Retinoid compounds are involved in the modulation of a wide variety of cellular processes such as proliferation, differentiation and apoptosis. Retinoid compounds have been investigated for use as cancer chemotherapeutic agents, but undesirable side effects have been problematic. Arotinoid compounds are a class of aromatic retinoid compounds. Arotinoid compounds have high biological activity but also impart undesirable toxicity. For example, the structure of TTNPB is also shown below.

Toxicity has, however, been a significant obstacle to developing retinoic acid and the analogs thereof. (See Biesalski H K, Toxicology, 57:117-161 (1989)). The observed side effects include: teratogenicity, hepatotoxicity, blood lipid abnormalities, scaly skin, hair loss and headaches. Other research has sought to discover new retinoic acid analogs having increased potency and/or reduced toxicity for use as cancer preventative agents. For example, it has been reported that N-(4-hydroxyphenyl) retinamide (“4-HPR”) displays chemopreventive activity toward breast cancer. (See Moon et al., Cancer Res, 39:1339-1346 (1979)). It has also been reported that the combination of 4-HPR and calcium glucarate has increased and synergistic breast cancer chemopreventive activity in carcinogen-induced rat mammary tumors. (See, Abou-Issa H M et al., Proc Natl Acad Sci USA, 85:4181-4184 (1988). However, the 4-HPR still displayed teratogenic potential in rat, mice and rabbit studies. (See Kenel M F et al., Teratogenicity of N-(4-hydroxyphenyl)-all-trans Retinamide in Rats and Rabbits, Teratogenesis, Carcinogenesis and Mutagenesis, 8:1-11 (1988))(See also Kochhar D M et al., Retinamides: Hydrolytic Conversion of Retinoylglycine to Retinoic Acid in Pregnant Mice Contributes to Teratogenicity, Teratology, 45:175-185 (1992)). It has also been reported that 4-HPR impairs night vision in human patients. (See Kaiser-Kupter M I et al., Abnormal Retinal Function Associated with Fenretinide, A Synthetic Retinoid Renretinide (HPR), Eur J Cancer Clin Oncol, 25:805-808 (1989)).
The structure of 4-HPR is shown below.

The ketone analog of 4-HPR is 4-HBR. The structure of 4-HBR is shown below. The properties (and synthesis thereof) of 4-HBR is disclosed in U.S. Pat. No. 6,117,845 to Clagett-Dame et al., which also discloses synthesis of various sugar-analogs of 4-HBR.
4-HBR and analogs thereof possess anti-neoplastic activity and are useful in preventing (i.e., prophylactic treatment) and/or treating neoplastic growth in mammals.
Despite recent advances in synthesis of stable and active analogs of retinoid acid, there remains a need for more potent and less toxic analogs and derivatives of retinoic acid and TTNPB, particularly such drugs useful for prophylactic treatment and treatment of many cancers including breast cancer.